EP0250264A1 - Inhibiteurs de dopamine-bêta-hydroxylase à effet irréversible - Google Patents

Inhibiteurs de dopamine-bêta-hydroxylase à effet irréversible Download PDF

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Publication number
EP0250264A1
EP0250264A1 EP87305476A EP87305476A EP0250264A1 EP 0250264 A1 EP0250264 A1 EP 0250264A1 EP 87305476 A EP87305476 A EP 87305476A EP 87305476 A EP87305476 A EP 87305476A EP 0250264 A1 EP0250264 A1 EP 0250264A1
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EP
European Patent Office
Prior art keywords
ethynyl
formula
acid salt
hydroxybenzeneethanamine
hydrochloric acid
Prior art date
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Withdrawn
Application number
EP87305476A
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German (de)
English (en)
Inventor
Pamela Anne Chambers
Lawrence Ivan Kruse
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP0250264A1 publication Critical patent/EP0250264A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
    • C07C57/42—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings having unsaturation outside the rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te

Definitions

  • This invention relates to novel compounds that irreversibly inhibit dopamine-a-hydroxylase, and novel pharmaceutical compositions, and methods for inhibiting dopamine-ß-hydroxylase.
  • tyrosine is converted in three steps to norepinephrine (NE). Intermediates are dihydroxyphenylalanine (DOPA) and dopamine (DA). Dopamine is hydroxylated to norepinephrine by dopamine-ß-hydroxylase (DBH) in the presence of oxygen and ascorbic acid.
  • DOPA dihydroxyphenylalanine
  • DA dopamine
  • DBH dopamine-ß-hydroxylase
  • Inhibition of catecholamine activity decreases blood pressure. Weinshilboum, Mayo Clin. Proc. 55, 39 (1980), reviews compounds that inhibit catecholamine activity by acting upon adrenergic receptors. Alternatively, the catecholamine biosynthetic pathway can be suppressed at any of the three steps, resulting in reduced NE levels. In addition to producing an antihypertensive effect, inhibitors of NE synthesis are active as diuretics, natriuretics, cardiotonics, and vasodilators. Inhibition of DBH activity can have the added advantage of increasing DA levels, which as reported by Ehrreich et al., "New Antihypertensive Drugs," Spectrum Publishing, 1976, pp. 409-432, has selective vasodilator activity at certain concentrations.
  • DBH inhibitors also have been shown to reduce or prevent formation of gastric ulcers in rats by Hidaka et al., "Catecholamine and Stress,” edit. by Usdin et'al., Permagon Press, Oxford, 1976, pp. 159-165 and by Osumi et al., Japan J. Pharmacol 23, 904 (1973).
  • DBH inhibitors A number of reversible DBH inhibitors are known. These generally are divided into two classes, namely, metal chelating agents, which bind copper in the enzyme, and phenethylamine analogues. Rosenberg et al., "Essays in Neurochemistry and Neurpharmacology," Vol. 4, edit. by Youdim et al., John Wiley &'Sons, 1980, pp. 179-192, and Goldstein, Pharmacol. Rev. 18(1), 77 (1966), review DBH inhibitors.
  • Known reversible'DBH inhibitors include:
  • Bupicomide 5-(n-butyl)picolinamine
  • Ehrreich et al. "New Antihypertensive Drugs", Spectrum Publications, 1976, pg. 409-432, to be a DBH inhibitor that possesses the ability to lower blood pressure.
  • United States Patent No. 4,532,331 describes various 1-benzyl-2-aminomethylimidazole derivatives that inhibit DBH activity and includes pharmaceutical compositions containing these derivatives and methods of using these derivatives to inhibit DBH activity.
  • Non-specific, often toxic effects of known DBH inhibitors have obviated clinical use of these compounds.
  • Fusaric acid for example, is hepatotoxic. See, for example, Mariawa et al., Japan. Cir. J. 35, 339 (1971) and references cited therein.
  • the picolinic acid structure interacts with a number of metalloproteins and enzymes non-specifically to produce the observed side effects.
  • the present invention resides in the discovery that DBH is inhibited by substituted ß-ethynyl and ß-ethenyl benzeneethanamine compounds and that the DBH inhibition produced by these compounds is irreversible. These compounds are potent and produce prolonged DBH inhibition.
  • Presently preferred compounds of the invention include:
  • X 1 is hydrogen or para-C 1-4 alkoxybenzyloxy
  • R 2 is 1,3-propanedioic acid diC 1-4 alkyl ester, preferably diethyl ester, or 2,2-dimethyl-l,3-dioxane-4,6-dione
  • X is as described in Formula I, above.
  • Scheme I illustrates reaction of a substituted phenylmethylene compound (A) with a tri C 1-4 alkylsilylacetylene, Grignard, preferably trimethylsilylacetylene, followed by addition of a strong acid such as hydrochloric acid, to prepare substituted phenyl(trimethylsilylethynyl)methyl- propanedioic acid diethyl esters (B) or substituted 2,2-dimethyl-5-phenyl(trimethylsilylethynylmethyl)-1,3-dioxane-4,6-diones (C).
  • A substituted phenylmethylene compound
  • Grignard preferably trimethylsilylacetylene
  • Substituted ß-ethynylbenzenepropanoic acid compounds (D) then are prepared by heating at about 80 to 120°C formula (B) compounds with a strong base such as an alkali metal hydroxide, for example sodium hydroxide, acidifying this reaction mixture with strong acid, such as hydrochloric acid, to obtain the diacid, followed by heating at about 80 to 120°C the diacid with aqueous organic base such as triethylamine, aminopyridine, or, preferably, pyridine.
  • a strong base such as an alkali metal hydroxide, for example sodium hydroxide
  • strong acid such as hydrochloric acid
  • Formula (D) compounds also are prepared by heating at about 80 to 120°C a mixture of a formula (C) compound with an aqueous organic base such as triethylamine, aminopyridine, or, preferably, pyridine, then heating the mixture at about 40-60°C with potassium fluoride in a dipolar, aprotic solvent such as dimethylformamide, thereby producing a salt, and then acidifying the salt by addition of strong acid such as hydrochloric acid.
  • aqueous organic base such as triethylamine, aminopyridine, or, preferably, pyridine
  • the substituted ß-ethynylbenzenepropanoic acid compounds (D) thus formed next are heated at about 80 to 120°C with diphenylphosphorylazide, an organic base, preferably triethylamine, and a 4-C 1-4 alkoxybenzyl alcohol, such as 4-methoxybenzyl alcohol (PMBOH), to prepare substituted 2-(ethynyl-2-phenylethyl)carbamic acid, 4-methoxyphenylmethyl esters (E).
  • diphenylphosphorylazide an organic base, preferably triethylamine
  • a 4-C 1-4 alkoxybenzyl alcohol such as 4-methoxybenzyl alcohol (PMBOH)
  • Formula I compounds having a B-ethynyl group (F) are deprotected by addition of a saturated ethereal hydrochloride solution.
  • Formula (I) compounds having a ß-ethenyl group (H) are formed by hydrogenation of formula (E) compounds over Lindlar catalyst (palladium on calcium carbonate poisoned with lead) available from Aldrich Chemical Company to produce formula (G) compounds followed by deprotection of the formula (G) compounds by addition of a saturated ethereal hydrochloride solution.
  • Formula (I) compounds in which X is hydrogen or hydroxy at the 2 or 3 position can be prepared from formula (A) compounds wherein R 2 is a 1,3-propanedioic acid diC 1-4 alkyl ester or 2,2-dimethyl-l,3-dioxane-4,6-dione. According to the reactions of Scheme (I), however, Formula (I) compounds wherein X is 4-hydroxy must be formed from formula (A) compounds wherein R 2 is 2,2-dimethyl-l,3-dioxane-4,6-dione.
  • Starting formula (A) compounds that are phenylmethylene propanedioic acid diC l-4 alkyl esters (X is H) are available and can be prepared by known procedures.
  • Formula (A) compounds having an para-C 1-4 alkoxybenzyloxy group are prepared from corresponding hydroxy compounds by alkylation with a suitable alkoxybenzyl halide, such as methoxybenzyl chloride, by known processes.
  • the corresponding hydroxy compounds are available and can be prepared by known techniques.
  • Formula (A) compounds that are 2,2-dimethyl-l,3-dioxane-4,6-diones are prepared from corresponding alkoxybenzyloxybenzaldehydes by reaction with Meldrum's acid (2,2-dimethyl-l,3-dioxane-4,6-dione) according to known procedures.
  • Meldrum's acid 2,2-dimethyl-l,3-dioxane-4,6-dione
  • a methoxybenzyloxybenz- aldehyde in an organic solvent such as toluene is reacted with Meldrum's acid in the presence of glacial acetic acid and piperidine to yield methoxybenzyloxybenzaldehyde-1,3-dioxane-4,6-dione compounds of formula (A).
  • the present invention includes compounds of the following Formulae II, III, and IV that are useful in preparing Formula (I) compounds of the invention: in which:
  • the pharmaceutically acceptable acid addition salts of the Formula (I) compounds are formed with strong or moderately strong organic or inorganic acids by methods known in the art.
  • the base is reacted with an inorganic or organic acid in an aqueous miscible solvent such as ethanol with isolation of the salt by removing the solvent or in an aqueous immiscible solvent when the acid is soluble therein, such as ethyl ether or chloroform, with the desired salt separating directly or isolated by removing the solvent.
  • Exemplary of the salts which are included in this invention are maleate, fumarate, lactate, oxalate, methanesuifonate, ethanesulfonate, benzenesulfonate, tartrate, citrate, hydrochloride, hydrobromide, sulfate, phosphate and nitrate salts.
  • Presently invented also are methods of producing DBH inhibition in mammals, including humans, by administering an effective amount of a 8-ethynyl or B-ethenyl benzeneethamine compound of Formula (I).
  • DBH activity was assayed by a standard procedure for measuring the conversion of tyramine to octopamine in the presence of DBH. J.J. Pisano, et al., Biochim. Biophy. Acta, 43, 566-68 (1960).
  • Octopamine was assayed following sodium periodate oxidation to p-hydroxybenzaldehyde by measuring spectrophotometric absorbance at 330 nm.
  • the enzyme was incubated for up to 50 minutes with 10, 20, 40, or 80 M concentrations of ß-ethynyl-4-hydroxybenzeneethanamine. This compound of the invention produced concentration- dependent DBH inhibition. Additionally, the enzyme inhibition was time-dependent which indicates that compounds of the invention are irreversible DBH inhibitors.
  • Blood pressure also was monitored in spontaneously hypertensive rats given 100 mg/kg intraperitoneally B-ethynyl-3-hydroxybenzeneethanamine hydrochloride. Forty minutes following compound administration approximate thirty percent blood pressure reductions were observed. At 260 minutes after compound administration blood pressure remained decreased approximately ten percent.
  • Solid or liquid pharmaceutical carriers can be employed.
  • Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil, saline, and water.
  • the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit.
  • the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.
  • the pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products.
  • Doses of the present compounds in a pharmaceutical dosage unit will be an efficacious, nontoxic quantity selected from the range of 0.1-1,000 mg/kg of active compound, preferably 10-100 mg/kg.
  • the selected dose is administered orally, rectally, or by injection from one to six times daily, or continuously by infusion to a human patient in need of treatment.
  • Parenteral administration which uses lower dosages, is preferred.
  • the crude acid was heated at 170°C under argon until the evolution of carbon dioxide ceased.
  • the cooled melt was dissolved in ethyl acetate (50 ml) and the resulting solution was extracted with 10% aqueous sodium hydroxide solution.
  • the ethyl acetate extracts were washed with water, dried, treated with activated carbon to yield (76%) ß-ethynylbenzenepropanoic acid as a crystalline solid: mp 83-86°C.
  • the ethanol solution was diluted with water (100 ml) and extracted with ethyl acetate.
  • the aqueous phase was cooled and acidified to pH 2 with 12N HC1 and the product was extracted with ethyl acetate.
  • the ethyl acetate extracts were washed with water, dried, treated with activated carbon, and concentrated to yield 3.32 g (65%) of ß-(ethynyl-3-(4-methoxyphenylmethoxy)-benzenepropanoic acid: mp. 141-142°C.
  • An oral dosage form for administering the presently invented compounds is produced by screening, mixing, and filling into a hard gelatin capsule the ingredients in the proportions shown in Table III, below.
  • sucrose, calcium sulfate dihydrate and B-ethynylbenzeneethanamine shown in Table IV below are mixed and granulated in the proportions shown with a 10% gelatin.solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into 2 tablets.
  • ß-ethynyl-3-hydroxybenzeneethanamine hydrochloride 75 mg, is dispursed in 25 ml of normal saline to prepare an injectable preparation.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP87305476A 1986-06-19 1987-06-19 Inhibiteurs de dopamine-bêta-hydroxylase à effet irréversible Withdrawn EP0250264A1 (fr)

Applications Claiming Priority (2)

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US87604386A 1986-06-19 1986-06-19
US876043 1986-06-19

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EP (1) EP0250264A1 (fr)
JP (1) JPS6322049A (fr)
AU (1) AU7445587A (fr)
DK (1) DK303887A (fr)
PT (1) PT85081A (fr)
ZA (1) ZA874396B (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000009115A1 (fr) * 1998-08-14 2000-02-24 Smithkline Beecham Corporation Ligands de recepteurs de grp
US7465804B2 (en) 2005-05-20 2008-12-16 Amgen Inc. Compounds, pharmaceutical compositions and methods for their use in treating metabolic disorders
US7572934B2 (en) 2007-04-16 2009-08-11 Amgen Inc. Substituted biphenyl GPR40 modulators
US7582803B2 (en) 2005-09-14 2009-09-01 Amgen Inc. Conformationally constrained 3-(4-hydroxy-phenyl)-substituted-propanoic acids useful for treating metabolic disorders
US7649110B2 (en) 2004-02-27 2010-01-19 Amgen Inc. Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders
US7687526B2 (en) 2006-09-07 2010-03-30 Amgen Inc. Benzo-fused compounds for use in treating metabolic disorders
US7714008B2 (en) 2006-09-07 2010-05-11 Amgen Inc. Heterocyclic GPR40 modulators
US8030354B2 (en) 2007-10-10 2011-10-04 Amgen Inc. Substituted biphenyl GPR40 modulators
US8450522B2 (en) 2008-03-06 2013-05-28 Amgen Inc. Conformationally constrained carboxylic acid derivatives useful for treating metabolic disorders
US8748462B2 (en) 2008-10-15 2014-06-10 Amgen Inc. Spirocyclic GPR40 modulators

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2555167Y2 (ja) * 1989-12-29 1997-11-19 大阪瓦斯株式会社 電気二重層キヤパシタ

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0011608A1 (fr) * 1978-08-30 1980-05-28 Astra Läkemedel Aktiebolag Amine allénique et ses sels d'addition acides, procédé pour leur préparation, préparations pharmaceutiques les contenant et l'utilisation de ces composés pour la préparation de compositions pharmaceutiques
EP0145361A2 (fr) * 1983-11-21 1985-06-19 McNeilab, Inc. Dérivés d'acétylène pour le traitement de l'hypertension et de l'angine
US4537974A (en) * 1984-09-26 1985-08-27 Hughes Aircraft Company Diethynylated phenylbenzimidazole compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0011608A1 (fr) * 1978-08-30 1980-05-28 Astra Läkemedel Aktiebolag Amine allénique et ses sels d'addition acides, procédé pour leur préparation, préparations pharmaceutiques les contenant et l'utilisation de ces composés pour la préparation de compositions pharmaceutiques
EP0145361A2 (fr) * 1983-11-21 1985-06-19 McNeilab, Inc. Dérivés d'acétylène pour le traitement de l'hypertension et de l'angine
US4537974A (en) * 1984-09-26 1985-08-27 Hughes Aircraft Company Diethynylated phenylbenzimidazole compounds

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, vol. 107, July 1963, New York, B.M. BLOOM "Some structural considerations regarding compounds that influence monoamine metabolism" pages 878-890 *
CHEMICAL ABSTRACTS, vol. 65, no. 2, July 18, 1966, Columbus, Ohio, USA, BURGERet al. "1-Ethynylphenetylamine" column 3772, abstract-no. 3772c & J. Med. Chem., vol. 9, no. 4, 1966, pages 469 - 470 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000009115A1 (fr) * 1998-08-14 2000-02-24 Smithkline Beecham Corporation Ligands de recepteurs de grp
US7649110B2 (en) 2004-02-27 2010-01-19 Amgen Inc. Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders
US7816367B2 (en) 2004-02-27 2010-10-19 Amgen Inc. Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders
US7465804B2 (en) 2005-05-20 2008-12-16 Amgen Inc. Compounds, pharmaceutical compositions and methods for their use in treating metabolic disorders
US7582803B2 (en) 2005-09-14 2009-09-01 Amgen Inc. Conformationally constrained 3-(4-hydroxy-phenyl)-substituted-propanoic acids useful for treating metabolic disorders
US7687526B2 (en) 2006-09-07 2010-03-30 Amgen Inc. Benzo-fused compounds for use in treating metabolic disorders
US7714008B2 (en) 2006-09-07 2010-05-11 Amgen Inc. Heterocyclic GPR40 modulators
US8003648B2 (en) 2006-09-07 2011-08-23 Amgen Inc. Heterocyclic GPR40 modulators
US7572934B2 (en) 2007-04-16 2009-08-11 Amgen Inc. Substituted biphenyl GPR40 modulators
US8030354B2 (en) 2007-10-10 2011-10-04 Amgen Inc. Substituted biphenyl GPR40 modulators
US8450522B2 (en) 2008-03-06 2013-05-28 Amgen Inc. Conformationally constrained carboxylic acid derivatives useful for treating metabolic disorders
US8748462B2 (en) 2008-10-15 2014-06-10 Amgen Inc. Spirocyclic GPR40 modulators

Also Published As

Publication number Publication date
DK303887A (da) 1987-12-20
JPS6322049A (ja) 1988-01-29
AU7445587A (en) 1987-12-24
PT85081A (en) 1987-07-01
ZA874396B (en) 1988-04-27
DK303887D0 (da) 1987-06-15

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